Project Summary/Abstract Chagas disease continues to be the highest impact parasitic disease in Latin American and indeed a problem worldwide. Despite the availability of two, decades-old treatment options - benznidazole and nifurtimox - most Trypanosoma cruzi-infected individuals remain untreated and many of those will eventually die of complications of the disease. Among the primary reasons for the failure of these two compounds to be more widely used is the significant rate of adverse events and high variability in terms of efficacy. The experiments proposed in this application are based on the hypothesis that the current intensive treatment regimen of up to 60 consecutive, twice daily doses of compound, increases the rate of adverse events while also failing to effectively deal with parasite biology, in particular the new understanding of the role of dormancy in T. cruzi amastigotes in drug treatment failures. Proceeding from preliminary data documenting superior parasitological cure outcomes in mice treated less frequently but over a longer time period, the work outlined in this proposal seeks to develop an optimized and highly dependable treatment regimen in mice and then the use this protocol to assess treatment outcomes in naturally infected rhesus macaques. The ultimate goal of this project is to develop a protocol using existing, known to be effective compounds that increases the efficacy and thus the usage of such compounds in human infection. In the current environment of limited new clinical candidates, and the recent failure in human clinical trials of some of these candidates (also using a 60 day intensive dosing protocol), our approach should provide the most rapid path to the more effective treatment of T. cruzi infection in humans.